The invention relates generally to therapeutic proteins which include insulin, an insulin analog, an insulin fragment or variant thereof having insulin activity, fused to albumin or fragments or variants of albumin. The invention encompasses polynucleotides encoding therapeutic albumin-insulin fusion proteins, therapeutic albumin-insulin fusion proteins, compositions, pharmaceutical compositions, formulations and kits. Host cells transformed with the polynucleotides encoding therapeutic albumin-insulin fusion proteins are also encompassed by the invention, as are methods of making the albumin-insulin fusion proteins of the invention using these polynucleotides, and/or host cells.
Albumin is responsible for a significant proportion of the osmotic pressure of serum and also functions as a carrier of endogenous and exogenous ligands. Human serum albumin (HSA, or HA), is a protein of 585 amino acids in its mature form (as shown in FIG. 1A-D). At present, HA for clinical use is produced by extraction from human blood. The production of recombinant HA (rHA) in microorganisms has been disclosed in EP 330 451 and EP 361 991.
Therapeutic proteins in their native state or when recombinantly produced, such as insulin, are typically labile molecules exhibiting short shelf-lives, particularly when formulated in aqueous solutions. The instability in these molecules when formulated for administration dictates that many of the molecules must be lyophilized and refrigerated at all times during storage, thereby rendering the molecules difficult to transport and/or store. Storage problems are particularly acute when pharmaceutical formulations must be stored and dispensed outside of the hospital environment.
Recombinantly produced therapeutic proteins such as insulin also may exhibit a short half-life in vivo, for example after being administered to a patient. Therapeutic proteins such as insulin which exhibit a longer-lived activity in vivo are desirable because they permit longer time periods between dosing in a patient.
Few practical solutions to the storage problems of labile protein molecules have been proposed. Accordingly, there is a need for stabilized, long lasting formulations of proteinaceous therapeutic molecules such as insulin that are easily dispensed, preferably with a simple formulation requiring minimal post-storage manipulation. Furthermore, there is a need for therapeutic proteins such as insulin which exhibit longer-lived activity after being administered to a patient.